The major long-term objective of this work is to provide data and knowledge that can be used to maximize the beneficial effects of fluoride with the minimum degree of unwanted side effects. Previous studies supported by this grant have shown that the levels of fluoride in the oral fluids, and the developing enamel are direct functions of plasma fluoride levels. Thus, the development and severity of dental fluorosis and perhaps the cariostatic effect of the ion are dependent on systemic fluoride levels. Several studies of factors that may influence plasma and other tissue fluoride levels are proposed for the next grant period. The influence of postnatal fluoride intake on the balance and tissue levels of fluoride in rat neonates will be determined. It is hypothesized that, due to skeletal-extracellular fluid fluoride dynamics, neonates may be in a strongly positive on negative balance depending on the level of intake. The only environmental variable taken into account when deciding the appropriate water fluoride level for a community is the average regional temperature. One of the proposed studies will examine the effects of water intake on the metabolism and balance of fluoride. Thus it will provide data relevant to the fluoridation of water supplies for the prevention of dental caries. Further studies on the transmucosal migration of fluoride in the GI tract will be conducted for the purpose of determining whether there are conditions which lead to the net loss of systemic fluoride via this route. Other studies will examine more closely the relationship between the functional mass of the kidneys and the chronic metabolism and retention of fluoride. The concept of a skeletal fluoride steady state which holds that when intake is constant on a chronic basis the skeleton largely or completely loses its ability to accumulate the ions, will be critically examined. Further studies of the cariostatic effect of fluoride will be conducted. These studies will determine the influence of fluoride on the oral microbial ecology and relate the effects to the level of cariostasis. Other studies will determine the cariostatic effect of fluoride given systemically or pre-eruptively compared to the effects produced by post-eruptive fluoride exposure alone or to the effects produced by both pre- and post- eruptive exposure. The proposed studies will thus add significantly to our knowledge of several aspects of the metabolism, toxicity and cariostatic mechanism of fluoride.